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Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway
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Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway
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Journal Article
Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway
2018
Overview
ObjectivesTo investigate the role of tyrosine kinase Fyn in the development of osteoarthritis (OA) and the underlying mechanisms, and to define whether targeting Fyn could prevent OA in mice.MethodsCartilage samples from normal and aged mice were analysed with proteome-wide screening. Fyn expression was examined with immunofluorescence in human and age-dependent or experimental mouse OA cartilage samples. Experimental OA in Fyn-knockout mice was induced by destabilisation of the medial meniscus. Primary cultured mouse chondrocytes were treated with proinflammatory cytokine interleukin-1β. The inhibitor of Src kinase family, AZD0530 (saracatinib), and inhibitor of Fyn, PP1, were used to treat experimental OA in mice.ResultsFyn expression was markedly upregulated in human OA cartilage and in cartilage from aged mice and those with post-traumatic OA. Fyn accumulates in articular chondrocytes and interacts directly with and phosphorylates β-catenin at Tyr142, which stabilises β-catenin and promotes its nuclear translocation. The deletion of Fyn effectively delayed the development of post-traumatic and age-dependent OA in mice. Fyn inhibitors AZD0530 and PP1 significantly attenuated OA progression by blocking the β-catenin pathway and reducing the levels of extracellular matrix catabolic enzymes in the articular cartilage.ConclusionsFyn accumulates and activates β-catenin signalling in chondrocytes, accelerating the degradation of the articular cartilage and OA development. Targeting Fyn is a novel and potentially therapeutic approach to the treatment of OA.
Subject
/ Animals
/ Arthritis, Experimental - enzymology
/ Arthritis, Experimental - prevention & control
/ Benzodioxoles - pharmacology
/ Benzodioxoles - therapeutic use
/ Cartilage, Articular - enzymology
/ Enzyme Inhibitors - pharmacology
/ Enzyme Inhibitors - therapeutic use
/ Humans
/ Molecular Targeted Therapy - methods
/ Osteoarthritis - prevention & control
/ Proto-Oncogene Proteins c-fyn - antagonists & inhibitors
/ Proto-Oncogene Proteins c-fyn - deficiency
/ Proto-Oncogene Proteins c-fyn - genetics
/ Proto-Oncogene Proteins c-fyn - physiology
/ Pyrimidines - therapeutic use
/ Quinazolines - therapeutic use
